Ocular Pharmacokinetic/Pharmacodynamic Modeling for Timolol in Rabbits Using a Telemetry System

Sakanaka, Koji; Kawazu, Kouichi; Tomonari, Masahide; Kitahara, Takashi; Nakashima, Makoto; Nishida, Koyo; Nakamura, Junzo; Sasaki, Hidetada; Higuchi, Shun

doi:10.1248/bpb.31.970

Cited by 9 publications

(17 citation statements)

References 17 publications

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“…Implanted rabbits were used repeatedly after cessation of each drug. This instillation time and measurement period were the same as our previous study, 7) in which IOP values (base line value; 20.7 mmHg) did not alter after vehicle instillation.…”

Section: Drug Disposition In Aqueous Humormentioning

confidence: 80%

“…6,7) Briefly, 25 ml of drug solution (mixture containing 0.01% bunazosin and 0.5% timolol in PBS) was carefully instilled in the middle of the lower conjunctival sac of unanaesthetized normal rabbits placed in restraint boxes. The rabbits were sacrificed with an overdose of sodium pentobarbital at the designated time after drug instillation.…”

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

“…6,7) Briefly, for bunazosin determination a 50 ml aliquot of the aqueous humor was added to 1 ml acetonitrile containing prazosin hydrochloride (20 nM) as an internal standard. After mixing, each mixture was centrifuged at 8000ϫg for 5 min, and the supernatant (100 ml) was diluted with 200 ml of water.…”

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

“…7) Briefly, the implanted telemetry transmitter sent IOP information to a receiver (RPC-1; Data Science International). IOP values were determined by the 15 min-average of IOP data.…”

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

“…In the previous reports, we have succeeded in developing two ocular PK/PD models for anti-glaucoma drugs after instillation into rabbits. One is the model for an a 1 -adrenergic antagonist, bunazosin, 6) and the other is for a b-adrenergic antagonist, timolol, 7) but no ocular PK/PD model for multidrug therapy for the eye has been devised. The models for bunazosin and timolol each include aqueous humor dynamics based on each action mechanism, which are different from one another; therefore, a combined ocular PK/PD model after instillation of a combination of multiple drugs must be able to be constructed by including each action mechanism.…”

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confidence: 99%

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Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

Sakanaka

Kawazu

Tomonari

et al. 2008

Biological & Pharmaceutical Bulletin

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The current mainstay of glaucoma treatment is topical medications of ocular hypotensive effect drugs in controlling intraocular pressure (IOP) and preserving visual field. IOP is mainly determined by the aqueous humor dynamics, which is the coupling of aqueous humor formation in the ciliary body and its drainage through the uveoscleral route and the trabecular meshwork route.1) The action mechanisms of anti-glaucoma drugs are well known and classified into several action mechanisms 2,3) : b-adrenergic antagonists (e.g., timolol, betaxolol), carbonic anhydrase inhibitors (e.g., dorzolamide), and a 2 -adrenergic agonists (e.g., apraclonidine, brimonidine) that suppress aqueous humor formation; prostaglandin FP receptor agonists (e.g., latanoprost, travoprost), prostamides (e.g., bimatoprost), and a 1 -adrenergic antagonists (bunazosin), which promote aqueous humor outflow through the uveoscleral route; and cholinomimetics (e.g., pilocarpine) responsible for promoting aqueous humor outflow through the trabecular meshwork route as a result of contraction of the ciliary muscle.It is also a common practice to use multiple anti-glaucoma drugs in combination to achieve target IOP lowering when a favorable response is not obtained by monotherapy. 4) In order to comprehend the result of multidrug treatment, some comparative studies on the combined effects of drugs were reported. 4,5) However, in multidrug therapy, without experiments it has been impossible to determine the strength and duration of the ocular hypotensive effect quantitatively.Pharmacokinetic/pharmacodynamic (PK/PD) models allow us to predict quantitatively both the drug concentration and pharmacological effect after administration of drugs. In the previous reports, we have succeeded in developing two ocular PK/PD models for anti-glaucoma drugs after instillation into rabbits. One is the model for an a 1 -adrenergic antagonist, bunazosin, 6) and the other is for a b-adrenergic antagonist, timolol, 7) but no ocular PK/PD model for multidrug therapy for the eye has been devised. The models for bunazosin and timolol each include aqueous humor dynamics based on each action mechanism, which are different from one another; therefore, a combined ocular PK/PD model after instillation of a combination of multiple drugs must be able to be constructed by including each action mechanism.In the present study, we constructed a new combined ocular PK/PD model by including both the action mechanisms of bunazosin and timolol, and simulated the theoretical drug concentrations and ocular hypotensive effects after instillation of a combination of bunazosin and timolol into rabbits using the combined model and PK/PD parameters for each drug. In addition, to verify the reliability of the combined model, we confirmed the drug concentrations and ocular hypotensive effects measured by a telemetry system after instillation of the drug combination. The PD parameters for bunazosin were recalculated from the ocular hypotensive effects measured by the telemetry system in order to obtain...

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Section: Drug Disposition In Aqueous Humormentioning

confidence: 80%

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

“…7) Briefly, the implanted telemetry transmitter sent IOP information to a receiver (RPC-1; Data Science International). IOP values were determined by the 15 min-average of IOP data.…”

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

mentioning

confidence: 99%

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Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

Sakanaka

Kawazu

Tomonari

et al. 2008

Biological & Pharmaceutical Bulletin

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Pharmacokinetics and Pharmacodynamics of Ocular Drugs

Dave

Bhansali

2016

Nano-Biomaterials for Ophthalmic Drug Delivery

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This chapter aims to provide the readers a systematic overview of the pharmacokinetics and pharmacodynamics of the drugs intended for ophthalmic use. The concepts of ocular pharmacokinetics and pharmacodynamics are briefly discussed in the introduction. The chapter begins with a discussion on the common anatomical and physiological factors such as blood–ocular and tear fluid–corneal barriers, as well as anterior segment drug loss; and the challenges these factor pose in describing ocular pharmacokinetics and pharmacodynamics. The biopharmaceutics of the ocular drugs describes common pathways of ocular drug absorption. Further, commonly employed routes of administration for ocular drugs are discussed with respect to the choice of the route, properties of the drug, the nature of the ocular disease, the targeted ocular tissue, and the pharmacokinetic behavior of the drugs administered through the route. The pharmacokinetic–pharmacodynamic models that describe the fate of ocular drugs are further reviewed. Finally, recent advances and current trends in understanding of the pharmacokinetics/pharmacodynamics of ocular drugs are discussed based on the reported findings of the scientific and medical community

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A short-term inhalation study to assess the reversibility of sensory irritation in human volunteers

et al. 2020

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Sensory irritation is an acute adverse effect caused by chemicals that stimulate chemoreceptors of the upper respiratory tract or the mucous membranes of the outer eye. The avoidance of this end point is of uttermost importance in regulatory toxicology. In this study, repeated exposures to ethyl acrylate were analyzed to investigate possible carryover effects from day to day for different markers of sensory irritation. Thirty healthy subjects were exposed for 4 h on five subsequent days to ethyl acrylate at concentrations permitted by the German occupational exposure limit at the time of study. Ratings of eye irritation as well as eye blinking frequencies indicate the elicitation of sensory irritation. These markers of sensory irritation showed a distinct time course on every single day. However, cumulative carryover effects could not be identified across the week for any marker. The rhinological and biochemical markers could not reveal hints for more pronounced sensory irritation. Neither increased markers of neurogenic inflammation nor markers of immune response could be identified. Furthermore, the performance on neurobehavioral tests was not affected by ethyl acrylate and despite the strong odor of ethyl acrylate the participants improved their performances from day to day. While the affected physiological marker, the increased eye blinking frequency stays roughly on the same level across the week, subjective markers like perception of eye irritation decrease slightly from day to day though the temporal pattern of, i.e., eye irritation perception stays the same on each day. A hypothetical model of eye irritation time course derived from PK/PD modeling of the rabbit eye could explain the withinday time course of eye irritation ratings repeatedly found in this study more precisely.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Ocular Pharmacokinetic/Pharmacodynamic Modeling for Timolol in Rabbits Using a Telemetry System

Cited by 9 publications

References 17 publications

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

Pharmacokinetics and Pharmacodynamics of Ocular Drugs

A short-term inhalation study to assess the reversibility of sensory irritation in human volunteers

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